Polyurethane foams for use in wound dressings

ABSTRACT

The invention provides a method of forming a polyurethane foam suitable for use as a wound-contacting layer, said method comprising: mixing 1 part by weight of an isocyanate-capped prepolymer having from 0.5 to 4.8 meq. NCO groups/g with from 0.4 to 1.0 parts by weight of water and an effective amount of a nonvolatile pharmaceutically acceptable acid to form a prepolymer mixture; allowing said prepolymer mixture to cure to form a foamed product; followed by drying the foamed product. The invention also provides acidified polyurethane foams obtainable by this method, and wound dressings comprising such foams.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Phase filing of Application Ser.No. PCT/GB00/00418, filed Feb. 10, 2000, which claims priority to UnitedKingdom Patent Application Ser. No. 9903097.5, filed Feb. 11, 1999.

This invention relates to polyurethane foams, and more particularly to amethod of making conformable, high-density polyurethane foams for use inwound dressings. The invention also relates to a wound dressing having awound-contacting layer formed from such a foam.

Polyurethane foams have been proposed for a number of uses in the priorart. For example, U.S. Pat. No. 3,903,232 discloses hydrophiliccross-linked polyurethane foams which are said to be useful for externalbody cleaning, for internal body usage and as absorptive products suchas diapers. The foams are prepared by reacting particularisocyanate-capped polyoxyethylene polyols having an isocyanatefunctionality greater than 2 with large amounts of an aqueous reactant,preferably water.

EP-A-0171268 discloses a dressing for use in deep wounds, which dressingcomprises individual pieces of absorbent hydrophilic foam containedwithin a porous bag formed from an apertured polymeric film. Theabsorbent foam is preferably a hydrophilic polyurethane foam which canbe made from HYPOL (Registered Trade Mark) isocyanate-capped polyetherprepolymer marketed by W.R. Grace & Co., and non-ionic surfactants.

According to EP-A-0171268, the fact that the foam is present in the formof individual pieces confers on the dressing the property of being ableto conform to the contours of a wound cavity both on initial applicationof the dressing and subsequently following absorption of body fluids. Itis said that existing commercially available foams, if used as a singlepiece, have too high a density to possess the required degree ofconformability.

U.S. Pat. No. 4,339,550 discloses a hydrophilic foam composition whichis prepared by the “in situ” reaction of an isocyanate-capped polyetherprepolymer having a functionality of from about 2 to about 8, water, anda chemically compatible, essentially non-polar, volatile organiccompound. The foam is stated to be capable of achieving a sustained,controlled release of the volatile materials from the foamed structure.Suitable “control release” ingredients include polyols, such aspropylene glycol and glycerine.

EP-A-0335669 discloses a hydrophilic foam composition comprising the “insitu” reaction product of an isocyanate-capped polyether prepolymer, ahydrophilic agent capable of absorbing water, an adjuvant comprising analcohol, a wetting agent and water. One application which is proposedfor the foam composition is in the manufacture of wound dressings. Thecomposition is said to carry the adjuvant releasably, so that at least aportion of the adjuvant is released into an external liquid (e.g. woundexudate) with which the foam composition comes into contact.

A wide range of prepolymer, hydrophilic agents, adjuvants and wettingagents are proposed in EP-0335669. Suitable prepolymers are said toinclude prepolymers having an NCO content as high as 2.55 meq/g or aslow as 0.5 to 0.9 meq/g. Water soluble monohydric, dihydric andpolyhydric alcohols are all said to be suitable adjuvants, but glycerolis preferred, and the majority of the examples involve the use ofglycerol. The sole example in which a monohydric alcohol is employed asthe adjuvant involves the use of a prepolymer having an NCO content of1.6 meq/g. The resulting product is said not to be acceptable because of“gross porosity”.

EP-A-0541391 describes a method of forming a polyurethane foam suitablefor use as a wound-contacting layer, the method comprising mixing 1 partby weight of an isocyanate-capped prepolymer having from 0.5 to 1.2 meqNCO groups/g with from 0.4 to 1.0 parts by weight of water in thepresence of from 0.05 to 0.4 parts by weight of a C₁ to C₃ monohydricalcohol, and then drying the product such that the amount ofwater-soluble alcohol remaining in the product is less than 1% byweight. The resulting foam has high density and conformability.

GB-A-1417962 discloses a non-reticulated polyurethane foam material, thefoam cells adjacent to at least one surface of which are irreversiblypartially collapsed relative to foam cells remote from said surface. Thespecification notes that polyurethane foam can be reversibly deformed orcompressed to reduce the thickness up to a certain extent, but theoriginal thickness will be recovered upon washing or steam heating. Incontrast, the “irreversibly partially collapsed” cells are formed byapplying a greater degree of compression, but not so great a degree ofcompression as to cause the cells to collapse completely or fuse.

According to GB-A-2253628, the foams disclosed in GB-A-1417962 aresuitable for the treatment of moderately exuding wounds, but they maynot have sufficient absorbency to absorb all the exudate from heavilyexuding wounds. GB-A-2253628 further reports that an attempt to increasethe absorbency of the known foam by incorporating an alginate duringmanufacture of the foam was unsuccessful. The alginate was said to bedegraded, with consequent impairment of its absorbent and haemostaticproperties. A deterioration in the appearance of the foam was alsonoted. However, GB-A-2253628 teaches that alginate may be used toenhance the absorbency of a polyurethane foam, after the foam hasalready been formed. Thus, the specification discloses a polyurethanefoam which is impregnated with alginate, for example by spreading analginate gel onto the surface of the foam, or immersing the foam in asolution of alginate.

In contrast to the teaching of GB-A-2253628, we have found thatalginates can advantageously be incorporated during the production ofpolyurethane foams, if the foam is formed by mixing an isocyanate-cappedprepolymer with a relatively small amount of water. Although theaddition of alginate does not substantially increase the absorbency ofthe polyurethane foam (as measured on a weight per weight basis), it hasbeen found that polyurethane foams containing alginate generally havesmaller, more uniform cells, and higher densities.

Accordingly, the present invention provides a method of forming apolyurethane foam suitable for use as a wound-contacting layer, themethod comprising mixing one part by weight of an isocyanate-cappedprepolymer having from 0.5 to 4.8 meq NCO groups/g with from 0.4 to 1.0parts by weight of water, characterised in that the mixture furthercontains from 0.2 to 20% by weight of alginic acid or a salt thereofPreferably, the alginic acid or alginate salt is present in an amount offrom 0.5 to 10% by weight, more preferably 0.5 to 5% by weight, e.g.from 0.75 to 2.5% by weight.

In particularly preferred embodiments, the isocyanate-capped prepolymerhas from 0.5 to 1.2 meq. NCO groups/g.

Preferably, the step of mixing is carried out in the presence of from0.05 to 0.4 parts by weight of a C₁ to C₃ monohydric alcohol. Subsequentdrying of the foam preferably results in a product containing less than1% by weight of the monohydric alcohol.

The use of a relatively small amount of water in accordance with thepresent invention produces an initial reaction mixture of relativelyhigh initial viscosity. Carbon dioxide formed by hydrolysis ofisocyanate end groups is therefore trapped, producing a foamed hydrogel.

The present invention also provides a polyurethane foam which issuitable for use as a wound-contacting layer, the foam having a densityof at least 0.28 g/cm³, and containing from 0.2 to 20% by weight ofalginic acid or a pharmaceutically acceptable salt thereof, generallyuniformly distributed throughout said foam.

Foams produced according to the method of the invention preferably havea density of at least 0.3 g/cm³. Particularly preferred foams have adensity in the range 0.3 to 1.0 g/cm³, e.g. about 0.5 g/cm³.

The foams of the invention also preferably have an elongation at breakof at least 150%, and more preferably at least 300%. Particularlypreferred foams according to the invention have an elongation at breakin the range from 500 to 2000%.

Depending on the proportions of other additives, the foam s of theinvention have an absorbency of at least 3 g saline/g, preferably atleast 5 g/g, and more preferably from 8 to 20 g/g. The foams are thushighly absorbent, yet conformable.

The foams of the invention also have the property of swelling andexpanding when water is absorbed. This is particularly advantageous in awound contact layer, because the swelling of the foam causes it to moveinwards towards the wound bed thus filling the wound cavity. Thisencourages the wound to heal from the base upwards and outwards, and itdiscourages epithelialization over the wound surface before the bed hasbeen filled with granulation tissue .

The degree of swelling of the foams of the present invention on completesaturation with an aqueous medium is typically at least 100% (expressedin terms of increase in volume), and preferably at least 200%. Preferredfoams swell by 400 to 800%. Despite this high degree of swelling,however the foams of the invention retain their integrity even afterabsorption of large quantities of water.

Moreover, the foams are found to have a morphology which is particularlyappropriate for low adherence wound dressings. The foams areopen-celled, the cells being very regular in size and shape, with verysmooth edges to the pores in the walls of the cells. Typically, thecells of the foams of the invention have an average diameter in therange 0.1 to 0.6 mm.

The prepolymer which is used in the method of the invention ispreferably an isocyanate-capped polyether, such as anethyleneoxy/propyleneoxy copolymer. A particularly suitable prepolymeris that available under Trade Mark HYPOL Hydrogel.

Although the preferred methods of the invention comprehend the use ofany of methanol, ethanol or propanol, the use of methanol isparticularly preferred. All three alcohols reduce the rate of reactionbetween the isocyanate-capped prepolymer and water, but the effect ofmethanol is more marked. A reduction of the reaction rate is desirablein order to facilitate mixing of the various components and spreading ofthe reaction mixture into a layer of suitable thickness for curing. Inaddition, the monohydric alcohol serves to end cap some of the NCO endgroups, preventing reaction with water to form the urea linkage. Thisalso gives a more flexible, conformable foam.

More preferably, one part by weight of the isocyanate-capped prepolymeris mixed with water in the presence of from 0.05 to 0.25 parts by weightof methanol or from 0.1 to 0.3 parts by weight of ethanol.

It will be appreciated that other components may be added to thereaction mixture in the method of the invention, in order to givedesired properties to the product. In particular, it is preferable toinclude a small proportion (e.g. up to 30% by weight of the wetcomposition) of a rubber, which may be either natural or synthetic. Thishas the effect of increasing the cure time for the polyurethane, andincreases extensibility, strength and tack.

Most importantly, it substantially reduces shrinkage of the gel ondrying, and it also improves bubble formation, producing more regular,smaller bubbles.

Preferably, the rubber is added in the form of a latex, ie. a suspensionor emulsion of the rubber in an aqueous medium. The latex will generallycomprise 40 to 70% solids by weight, e.g. 50 to 60% by weight. If thefoam is to be used as a wound contact layer, the rubber must of coursebe pharmaceutically acceptable.

Acrylic-based rubbers are particularly preferred. These are commerciallyavailable in the form of latexes, such as PRIMAL B-15J and RHOPLEX N-560(Registered Trade Marks), manufactured by the Rohm & Haas company.

In addition to the methanol or ethanol other alcohols, and particularlypolyols, may be included in the reaction mixture to produce a softer,more conformable foam. For example, a polyol sold by Bayer AG under theRegistered Trade Mark Levagel may be used. However, traces of suchalcohols are likely to remain in the free form after the foamingreaction, and these traces may be difficult to remove from the foammerely by heating. The use of higher boiling alcohols is thereforepreferably avoided if the foam is to be used as a wound contact layer,because of the likelihood that such alcohols will be leached from thefoam during use of the dressing. When used as or in wound dressings, thefoams of the invention contain less than 1% by weight of water solublealcohols, and more preferably less than 0.1% by weight. It isparticularly preferred that the foams of the invention are essentiallyfree of water soluble alcohols (e.g. less that 0.01% by weight).

For use as a wound-contact layer, the foams of the invention may alsoinclude topical medicaments and antiseptics, such as silversulfadiazine, povidone iodine, chlorhexidine acetate and chlorhexidinegluconate, as well as other therapeutically useful additives such aspolypeptide growth factors and enzymes.

The present invention also provides a wound dressing comprising a woundcontact layer formed from a polyurethane foam as described above, inconjunction with a water-repellant or water-impermeable backing layer.It is greatly preferred that the backing layer also be moisture vapourpermeable, as well as being extensible and conformable. A particularlysuitable material is a high density polyurethane foam, such as MEDFIX4003 or 4005 (Registered Trade Mark). These are polyurethane foams of ablocked toluene diisocyanate nature, and are predominantly closed cell.

A particularly advantageous presentation for the dressing of theinvention is as an island of wound-contact material on a backing layer,wherein at least the marginal portions of the backing layer are coatedwith adhesive. Any medically accepted, skin friendly adhesive issuitable, including acrylic, hydrocolloid, polyurethane and siliconebased adhesives.

The adhesive may be applied either continuously or discontinuously overthe marginal portions of the backing layer. Preferably, however, theadhesive is applied continuously over the whole of the backing layer ifthe backing layer is not itself impermeable to bacteria, so as to ensurethat the backing layer/adhesive combination is impermeable to bacteria

It is also preferred that the combination of adhesive and backing layerhave a minimum moisture vapour permeability of 400 g/m²/24 hrs, andpreferably at least 700 g/m²/24 hrs.

The preferred adhesive is a polyurethane gel material known as LEVAGEL(Registered Trade Mark) and marketed by Bayer AG. This adhesive is madeup of three components, namely a modified diphenylmethane diisocyanate,high molecular weight polyhydroxy polyether and a catalyst(dibutyltindilaurate). These three components may be mixed such that thegel contains 4-10 parts (preferably 4.6-6.4 parts) of the modifieddiphenylmethane diisocyanate, 99.9-99.9975 parts, (preferably99.94-99.995 parts) of the polyhydroxy polyether and 0.0025-0.1 parts(preferably 0.005-0.06 parts) of the catalyst.

The gel may be mixed by the methods given in U.S. Pat. No. 4,661,099 andapplied by conventional coating methods to the backing. The thickness ofthe gel layer may be between 0.01 mm and 1.0 mm, and preferably between0.05 mm and 0.5 mm, giving a coating weight of between 25 g/m² and 250g/m².

The dressing may also contain a wicking layer between the wound contactlayer and the backing layer. Such a wicking layer provides absorbency,but more importantly it encourages moisture to move from the woundfacing side of the dressing to the back of the dressing where it escapesout of the dressing through the breathable backing. It should have goodwicking properties so that moisture can be spread over as large asurface area as possible, thus increasing evaporation The overall effectof this layer is to draw moisture from the wound facing layer, thusdecreasing the chances of wound maceration, and to increase evaporationthrough the backing of the dressing

The wicking layer may be formed of several plies (which may or may notbe the same) if desired, but it is preferred that the total thickness ofthe wicking layer does not exceed 1 mm. It is also preferred that thewicking layer be substantially the same size and shape as thewound-facing layer, or slightly smaller than the wound-facing layer.

Suitable materials for the wicking layer include nonwoven, woven andknitted fabrics. Nonwoven viscose fabrics such as those conventionallyused for making nonwoven surgical swabs are preferred, but it will beunderstood that many alternative fabrics particularly other cellulosicfabrics) could be used in their place.

The dressings of the invention will generally be sterile and enclosed ina conventional bacteria-proof envelope. Sterilization may conventionallybe carried out using γ-irradiation, but other sterilization methods suchas electron beam sterilization may also be used.

The effect of addition of a nonvolatile acid on experimental curingrates of polyurethane foams for use in wound dressings is shown by thefollowing specific embodiments, which are non-limiting examples for thepurpose of illustration only.

EXAMPLE 1 (COMPARATIVE)

Methanol (6 g) was added to HYPOL (Registered Trade Mark) Hydrogelprepolymer (50 g; NCO content 0.5-1.2 meq/g) in a disposable cup andmixed thoroughly for a few seconds. Water (32 g) and Latex (12 g) werethen added to the HYPOL mixture and stirred vigorously. The foamingmixture was poured onto release paper and spread using a stainless steelhand spreader set at a gap of 2.2 mm. The foam was left to cure and thefoam sheet and release paper were placed in an oven (80° C.-100° C.) for30 min to drive off the water. After cooling, the foam, was lifted fromthe release paper, allowed to shrink, and replaced on the same paper.The foam was then kiss-cut to size and shape.

EXAMPLES 2-12

The procedure of Example 1 was repeated, but with the addition ofvarying amounts of sodium alginate and calcium alginate, as set out inthe following Table. The Table also shows the absorbency of the foamsproduced, as determined by the following method:

A sample of foam (approximately 3 g) is prepared and weighed, thenplaced in a pre-weighed cylindrical wire mesh basket (5 cm diameter, 9cm depth; 9 cm mesh size). The basket is formed from galvanised steelwire (approx. 0.95 mm thickness), and is closed at one end. The basketand sample are then completely submerged in 0.9% saline solution for 1hour. The basket is removed from the saline solution, and allowed todrain for 15 seconds, with the closed end down. The basket is thenweighed in order to determine the weight of the saturated sample.

Example Sodium alginate Calcium alginate Absorbency (g/g) 1 — — 11.4 20.5% — 16.1 3 1.0% — 15.5 4 2.5% — 16.4 5 5.0% — 14.6 6 10.0%  — 14.1 7— 1.0% 14.0 8 — 5.0% 13.4 9 — 10.0%  12.8 10 0.2% 0.8% 14.0 11 1.0% 4.0%13.4 12 2.0% 8.0% 13.1

It will be seen that the addition of comparatively small amounts ofsodium or calcium alginate results in a modest increase in absorbency(on a weight per weight basis), but absorbency decreases with greaterquantities of alginate. More importantly, however, the addition ofalginate gives rise to smaller and more uniform pores in the foam. Thiscan be seen in the accompanying figures which are scanning electronmicrographs at ×20 magnification.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a section through a foam according to Example 1, while

FIG. 2 shows a corresponding section through a foam according to Example3.

The greater uniformity of pore size has a number of benefits. Inparticular, the foams of the present invention are more consistent intheir absorbency, tensile strength, density and appearance, and theyhave a reduced tendency to display manufacturing faults such asspreading lines. Moreover, the smaller pore size also means that thefoams are of greater density. This, in turn, means that absorbency (on aweight per volume basis) is more substantially increased.

The above embodiments have been described by way of example only. Manyother embodiments of the present invention falling within the scope ofthe accompanying claims will be apparent to the skilled reader.

What is claimed is:
 1. A method of forming a polyurethane foam suitablefor use as a wound-contacting layer, said method comprising mixing onepart by weight of an isocyanate-capped prepolymer having from 0.5 to 4.8meq NCO groups/gram with from 0.4 to 1.0 parts by weight of water,wherein said mixture further contains from 0.2 to 20% by weight ofalginic acid or a salt thereof.
 2. A method according to claim 1,wherein the isocyanate-capped prepolymer has from 0.5 to 1.2 meq NCOgroups/gram.
 3. A method according to claim 1, wherein the step ofmixing is carried out in the presence of from 0.05 to 0.4 parts byweight of a C₁ to C₃ monohydric alcohol.
 4. A method according to claim3, wherein the monohydric alcohol is methanol.
 5. A method according toclaim 1, wherein the alginic acid salt is sodium alginate, calciumalginate, or a combination thereof.
 6. A method according to claim 1,wherein said prepolymer mixture contains from 0.5 to 10% by weight ofsaid alginic acid or salt thereof.
 7. A method according to claim 1,wherein said isocyanate-capped prepolymer is an isocyanate-cappedpolyether prepolymer.
 8. A method according to claim 7, wherein saidisocyanate-capped polyether prepolymer is an isocyanate-cappedethyleneoxy/propyleneoxy copolymer.
 9. A method according to claim 1wherein one part by weight of the isocyanate-capped prepolymer is mixedwith from 0.6 to 0.9 parts by weight water.
 10. A method according toclaim 3 wherein one part by weight of the isocyanate-capped prepolymeris mixed with water in the presence of from 0.05 to 0.25 parts by weightof methanol or from 0.1 to 0.3 parts by weight ethanol.
 11. Apolyurethane foam which is suitable for use as a wound-contacting layer,said foam having a density of at least 0.28 grams/centimeter³, andcontaining from 0.2 to 20% by weight of alginic acid or apharmaceutically acceptable salt thereof, generally uniformlydistributed throughout said foam.
 12. A polyurethane foam according toclaim 11, wherein said foam contains from 0.5 to 10% by weight of saidalginic acid or salt thereof.
 13. A polyurethane foam according to claim11 having a density in the range of from 0.32 to 0.48 grams/centimeter³.14. A polyurethane foam according to claim 11 having an elongation atbreak of at least 150%.
 15. A polyurethane foam according to claim 14having an elongation at break of from 500 to 2000%.
 16. A polyurethanefoam according to claim 11 having an absorbency of at least 10 gramssaline/gram.
 17. A polyurethane foam according to claim 11 having aswellability on absorption of water of at least 200% by volume.
 18. Apolyurethane foam according to claim 11, containing less than 0.01% byweight of water-soluble alcohols.
 19. A polyurethane foam according toclaim 11, wherein said alginic acid salt is sodium alginate, calciumalginate, or a combination thereof.
 20. A wound dressing having awound-contact layer formed from a polyurethane foam according to any oneof claims 1 to 19.